U.S. Pat. No. 4,374,829 discloses the compound enalapril maleate, which is a drug useful to treat hypertension. This patent also discusses methods of formulating drugs into pharmaceutical compositions such as tablets and capsules.
In order to manufacture pharmaceutical tablets or capsules, it is necessary to mix the active ingredient with inactive ingredients which may serve as binders, fillers, disintegrating agents, lubricants, and colorants or have other purposes. Inactive ingredients are also known as `excipients`. All of the inactive ingredients together (i.e., the totality of ingredients other than the active ingredient) are known as the `carrier`.
After the active ingredient is mixed with the carrier, the mix is made into the tablets on a table press or filled into gelatin capsules on a capsule filling machine. The processes of preparing the mix and making tablets or filling capsules are well known to those skilled in the art of pharmaceutical formulation.
One of the requirements for an acceptable pharmaceutical composition is that it must be stable, so as not to exhibit substantial decomposition of the active ingredient during the time between manufacture of the composition and use by the patient.
Surprisingly, it has been found that enalapril maleate is not compatible with most of the usual excipients, including most of those mentioned in U.S. Pat. No. 4,374,829. Decomposition of enalapril maleate is accelerated by most of these excipients, thus making it very difficult to formulate a stable table or capsule containing enalapril maleate.
The difficulty of formulating a stable composition containing enalapril maleate is confirmed by European Patent Application No. 92119896.6. That application discloses that a stable formulation can be made by reacting enalapril maleate with a sodium compound to convert the enalapril maleate into enalapril sodium plus disodium maleate. Stability data contained in this patent application demonstrates that the final composition containing enalapril sodium mixed with disodium maleate and other ingredients is far more stable than a similar composition containing enalapril maleate.
However, the formulations of European Application No. 92119896.6 have the disadvantage of requiring the step of converting the enalapril maleate into enalapril sodium plus disodium maleate.
In light of the foregoing, the object of the invention is to enable production of a stable pharmaceutical table or capsule containing enalapril maleate.